5-HT1F agonists

ABSTRACT

The present invention relates to substituted furo[3,2-b]pyridine compounds of formula I:                    
     or a pharmaceutical acid addition salt thereof; where; 
     R is                    
     E—D is C═CH or CH—CH 2 ; 
     R 1  is hydrogen or C 1 -C 4  alkyl; 
     R 2  is hydrogen, halo, hydroxy, —NR 3 R 4 , —SR 3 , —C(O)R 3 , —C(O)MR 3 R 4 , —NR 3 SO 2 R 5 , —NHC(Q)NR 3 R 4 , —NHC(O)OR 3 , or —NR 3 C(O)R 5 ; 
     R 3 , R 4 , and R 5  are independently hydrogen, C 1 -C 4  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or —(CH 2 ) n aryl; or R 3  and R 4  combine, together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine, or thiomorpholine ring; 
     n is 0, 1, 2, 3, 4, 5, or 6; and 
     Q is O or S. 
     The present invention further relates to pharmaceutical. formulations containing compounds formula I and to the use of compounds of formula I for activating 5-HT 1F  receptors, inhibiting neuronal protein extravasation, and treating and/or preventing migraine in a mammal.

The present PCT national stage application claims priority to U.S.Provisional 60/122,016, filed Feb. 26, 1999.

Theories regarding the pathophysiology of migraine have been dominatedsince 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry,39:737-63, 1938. They proposed that the cause of migraine headache wasvasodilatation of extracranial vessels. This view was supported byknowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT₁agonist which does not cross the blood-brain barrier, contract cephalicvascular smooth muscle and are effective in the treatment of migraine.Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work byMoskowitz has shown, however, that the occurrence of migraine headachesis independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia which innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers. Neurology,43 (suppl. 3):S16-S20 1993.

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast seven receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses one of these 5-HT₁ receptorsubtypes, named 5-HT_(1F), was isolated by Kao and coworkers. Proc.Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT_(1F) receptor exhibitsa pharmacological profile distinct from any serotonergic receptor yetdescribed. The high affinity of sumatriptan at this subtype, K_(i)=23nM, suggests a role of the 5-HT_(1F) receptor in migraine.

This invention relates to novel 5-HT_(1F) agonists which inhibit peptideextravasation due to stimulation of the trigeminal ganglia, and aretherefore useful for the treatment of migraine and associated disorders.

The present invention relates to a compound of formula I:

and pharmaceutical acid addition salts thereof, where;

R is

E—D is C═CH or CH—CH₂;

R¹ is hydrogen or C₁-C₄ alkyl;

R² is hydrogen, halo, hydroxy, —NR³R⁴, —SR³, —C(O)R³, —C(O)NR³R⁴,—NR³SO₂R⁵, —NHC(Q)NR³R⁴, —NHC(O)OR³, or —NR³C(O)R⁵;

R³, R⁴, and R⁵ are independently hydrogen, C₁-C₄ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, or —(CH₂)_(n)aryl; or R³ and R⁴ combine, together withthe nitrogen to which they are attached, form a pyrrolidine, piperidine,piperazine, 4-substituted piperazine, morpholine, or thiomorpholinering;

n is 0, 1, 2, 3, 4, 5, or 6; and

Q is O or S.

This invention also relates to a pharmaceutical formulation comprising acompound of formula I, or a pharmaceutical acid addition salt thereof,and a pharmaceutical carrier, diluent, or excipient.

In addition, the present invention relates to a method for activating5-HT_(1F) receptors in mammals comprising administering to a mammal inneed of such activation an effective amount of a compound of formula I,or a pharmaceutical acid addition salt thereof.

Moreover, the current invention relates to a method for inhibitingneuronal protein extravasation comprising administering to a mammal inneed of such inhibition an effective amount of a compound of formula I,or a pharmaceutical acid addition salt thereof.

One embodiment of this invention is a method for increasing activationof the 5-HT_(1F) receptor for treating a variety of disorders which havebeen linked to decreased neurotransmission of serotonin in mammals.Included among these disorders are depression, migraine pain, bulimia,premenstrual syndrome or late luteal phase syndrome, alcoholism, tobaccoabuse, panic disorder, anxiety, general pain, post-traumatic syndrome,memory loss, dementia of aging, social phobia, attention deficithyperactivity disorder, disruptive behavior disorders, impulse controldisorders, borderline personality disorder, obsessive compulsivedisorder, chronic fatigue syndrome, premature ejaculation, erectiledifficulty, anorexia nervosa, disorders of sleep, autism, mutism,trichotillomania, trigeminal neuralgia, dental pain or temperomandibularjoint dysfunction pain. The compounds of this invention are also usefulas a prophylactic treatment for migraine. Any of these methods employ acompound of formula I.

The use of a compound of formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of peptide extravasation in general or dueto stimulation of the trigeminal ganglia specifically, and for thetreatment of any of the disorders described above, are all embodimentsof the present invention.

The general chemical terms used throughout have their usual meanings.For example, the term “C₁-C₄ alkyd” refers to methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term“C₁-C₆” alkyl includes those groups listed for C₁-C₄ alkyl and alsorefers to saturated, straight, or branched hydrocarbon chains of 5 to 6carbon atoms. Such groups include, but are not limited to, pentyl,pant-2-yl, pent-3-yl, neopentyl, hexyl, and the like. The term “C₃-C₈cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl.

The term “C₂-C₆ alkenyl” refers to mono-unsaturated straight or branchedhydrocarbon chains containing from 2 to 6 carbon atoms and includes, butis not limited to, vinyl, allyl, 1-buten-4-yl, 2-buten-4-yl,1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-6-yl, 2-hexen-6-yl,3-hexen-6-yl, 4-hexen-6-yl and the like.

The term “C₂-C₆ alkynyl” refers to straight or branched hydrocarbonchains containing 1 triple bond and from 2 to 6 carbon atoms andincludes, but is not limited to, acetylenyl, propynyl, 2-butyn-4-yl,1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the like.

The terms “C₁-C₆ alkoxy” and “C₁-C₄ alkoxy” refer respectively to aC₁-C₆ alkyl and C₁-C₄ alkyl group bonded through an oxygen atom. Theterm “heteroaryloxy” refers to a heteroaryl or substituted heteroarylgroup bonded through an oxygen atom. The term “aryloxy” refers to aphenyl or substituted phenyl group bonded through an oxygen atom. Theterm “C₁-C₄ acyl” refers to a formyl group or a C₁-C₃ alkyl group bondedthrough a carbonyl moiety. The term “C₁-C₄ alkoxycarbonyl” refers to aC₁-C₄ alkoxy group bonded through a carbonyl moiety.

The term “aryl” refers to an optionally substituted phenyl.

The term “aryl” refers to an optionally substituted phenyl or optionallysubstituted heterocyclic ring.

The term “heterocyclic” is taken to mean an unsaturated 5- or 6-memberedring containing from 1 to 3 heteroatoms selected from: nitrogen, oxygenand sulfur, said ring optionally being benzofused. Heterocyclic ringsinclude furanyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl,oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl,thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and thelike. Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl,benzthiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl, andthe like.

The terms “substituted phenyl” and “substituted heterocycle” are takento mean that the cyclic moiety in either case is substituted once withhalo, cyano, nitro, C₁-C₄ acyl, trifluoromethane, trifluoromethoxy,C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, or C₁-C₄ alkyl, or two to fivesubstituents independently selected from the halo group.

The term “amino protecting group” as used in this specification refersto a substituents commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the acetyl group, thetrichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, urethane-type blocking groups such as benzyloxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), and the like; and like aminoprotecting groups. The species of amino protecting group employed is notcritical so long as the derivitized amino group is stable to thecondition of subsequent reactions on other positions of the molecule andcan be removed at the appropriate point without disrupting the remainderof the molecule. Further examples of groups referred to by the aboveterms are described by T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley and Sons, New York, N.Y., 1991, Chapter 7hereafter referred to as “Greene”.

The term “pharmaceutical” when used herein as an adjective, meanssubstantially non-toxic and substantially non-deleterious to therecipient.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipients and salt must be compatible with the activeingredient of the formulation (a compound of formula I).

The term “acid addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic acid. For exemplification of pharmaceutical acid addition saltssee, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm.Sci., 66:1, 1977. Since the compounds of this invention are amines, theyare basic in nature and accordingly react with any of a number ofinorganic and organic acids to form pharmaceutical acid addition salts.Since some of the free amines of the compounds of this invention aretypically oils at room temperature, it is preferable to convert the freeamines to their pharmaceutically acceptable acid addition salts for easeof handling and administration, since the latter are routinely solid atroom temperature.

The pharmaceutical acid addition salts of the invention are typicallyformed by reacting a compound of formula I with an equimolar or excessamount of acid. The reactants are generally combined in a mutual solventsuch as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol,benzene, and the like. The salts normally precipitate out of solutionwithin about one hour to about ten days and can be isolated byfiltration or other conventional methods.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and Acids commonly employed to formsuch salts are inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids, such as p-toluenesulfonic acid, methanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid, oxalic acid or fumaric acid.

The term “effective amount” means an amount of a compound of formula Iwhich is capable of activating 5-HT_(1F) receptors and/or inhibitingneuronal protein extravasation.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

All enantiomers, diastereomers, and mixtures thereof, are includedwithin the scope of the present invention. For example, the compounds offormula I where R is indolizidin-6-yl contain two chiral centers locatedin the bicyclic ring. One chiral center is located at the bridgeheadcarbon in the ring system, and the other is located in the CH groupbonded to the 3-position of the indole ring. For the purposes of thepresent application, the numbering system for naming the substituentsaround the indole ring and the R, R and S, S enantiomers are illustratedbelow where R¹ and R² are as defined above.

The following group is illustrative of compounds contemplated within thescope of this invention:

1)2-methyl-3-(2-[N′,N′-diethylamino]ethyl)-5-(4-propanesulfonylbenzamide)furo[3,2-b]pyridinehydrochloride;

2)2-n-butyl-3-(2-[N′-methyl-N′-benzylamino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridine;

3)2-isobutyl-3-(2-[N′-methyl-N′-cyclopropylmethylamino]ethyl)-5-(4-iodobenzamide)furo[3,2-b]pyridinenaphthalene-1-sulfonate;

4)2-s-butyl-3-(2-[N′-methyl-N′-(2-[1-propylpyrazol-4-yl]ethyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridineditoluoyltartrate;

5)2-methyl-3-(2-[N′-methyl-N′-s-butylaminoethyl)-5-isobutyramidefuro[3,2-b]pyridine;

6)2-methyl-3-(2-[N′-methyl-N′-(2-[pyridin-4-yl]ethyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinemalonate;

7)2-methyl-3-(2-[N′-methyl-N′-(2-[1-isbpropylpyrazol-4-yl]ethyl)amino]ethyl)-5-butyramidefuro[3,2-b]pyridinemandelate;

8)3-(2-[N′-methyl-N′-([4-bromothien-2-yl]methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinehydrochloride;

9)2-ethyl-3-(2-[N′-ethyl-N′-(2-[3-methylthiobenzofur-5-yl]ethyl)amino]ethyl)-5-(pyridine-2-carboxamide)furo[3,2-b]pyridine;

10)2-propyl-3-(2-[N′-isopropyl-N′-(3-[isobenzofur-2-yl]propyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridine;

11)2-methyl-3-(2-[N′-butyl-N′-([pyrrol-3-yl]methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinemaleate;

12)2-methyl-3-(2-[N′-methyl-N′-([5-cyanoimidazol-2-yl]methyl)amino]ethyl)-5-acetamidefuro[3,2-b]pyridinetrifluoroacetate;

13)2-methyl-3-(2-[N′-methyl-N′-([6-carboxamidopyrazin-2-yl]methyl)amino]ethyl)-5-propanecarboxamidefuro[3,2-b]pyridine;

14)2-methyl-3-(2-[N′-methyl-N′-([5-nitropyrimidin-2-yl]methyl)amino]ethyl)-5-(2-propanecarboxamide)furo[3,2-b]pyridine;

15)2-methyl-3-(2-[N′-methyl-N′-([5-dimethylaminopyridazin-3-yl]methyl)amino]ethyl)-5-butyramidefuro[3,2-b]pyridinebenzoate;

16)2-methyl-3-(2-[N′-methyl-N′-([indazol-5-yl]methyl)amino]ethyl)-5-pentanecarboxamidefuro[3,2-b]pyridine;

17)2-methyl-3-(2-[N′-methyl-N′-([quinolin-4-yl]methyl)amino]ethyl)-5-cyclopropanecarboxamidefuro[3,2-b]pyridine;

18)2-methyl-3-(2-[N′-methyl-N′-([isoquinolin-7-yl]methyl)amino]ethyl)-5-cyclobutanecarboxamidefuro[3,2-b]pyridine;

19)2-methyl-3-(2-[N′-methyl-N′-([quinoxalin-2-yl]methyl)amino]ethyl)-5-cyclopentanecarboxamidefuro[3,2-b]pyridinehexanoate;

20)2-methyl-3-(2-[N′-methyl-N′-([quinaxolin-5-yl]methyl)amino]ethyl)-5-cyclohexanecarboxamidefuro[3,2-b]pyridine;

21)2-methyl-3-(2-[N′-methyl-N′-([thiazol-2-yl]methyl)amino]ethyl)-5-cycloheptanecarboxamidefuro[3,2-b]pyridine;

22)2-methyl-3-(2-[N′-methyl-N′-([2-aminobenzothiazol-5-yl]methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinetrifluoromethanesulfonate;

23)2-methyl-3-(2-[N′-methyl-N′-([oxazol-5-yl]methyl)amino]ethyl)-5-(3-iodobenzamide)furo[3,2-b]pyridine;

24)2-methyl-3-(2-[N′-methyl-N′-([6-nitrobenzoxazol-2-yl]methyl)amino]ethyl)-5-(2-chlorobenzamide)furo[3,2-b]pyridinehydrobromide;

25)2-methyl-3-(2-[N′-methyl-N′-([1,4-benzodioxan-6-yl]methyl)amino]ethyl)-5-(2-chloropyridine-3-carboxamide)furo[3,2-b]pyridine;

26)2-isopropyl-3-(2-[N′-methyl-N′-([isoxazol-4-yl]methyl)amino]ethyl)-5-benzamidefuro[3,2-b]pyridine;

27)2-methyl-3-(2-[N′-methyl-N′-([benzisoxazol-3-yl]methyl)amino]ethyl)-5-(thiophene-2-carboxamide)furo[3,2-b]pyridine;

28)2-methyl-3-(2-[N′-methyl-N′-([1,3,4-oxadiazol-2-yl]methyl)amino]ethyl)-5-(furyl-3-carboxamide)furo[3,2-b]pyridine;

29)2-methyl-3-(2-[N′-methyl-N′-([1,2,3-triazol-4-yl]methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinetosylate;

30)3-(2-[N′-methyl-N′-((4-bromothien-2-yl)methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinehydrochloride;

31)2-ethyl-3-(2-[N′-ethyl-N′-((3-methylthiobenzofur-5-yl)ethyl)amino]ethyl)-5-(pyridine-2-carboxamide)furo[3,2-b]pyridine;

32)2-propyl-3-(2-[N′-isopropyl-N′-1-((isobenzofur-2-yl)prop-3-yl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridine;

33)2-methyl-3-(2-[N′-butyl-N′-(pyrrol-3-yl)methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinemaleate;

34)2-methyl-3-(2-[N′-methyl-N′-((5-cyanoimidazol-2-yl)methyl)amino]ethyl)-5-(4-acetamide)furo[3,2-b]pyridinetrifluoroacetate;

35)2-methyl-3-(2-[N′-methyl-N′-((6-carboxamidopyrazin-2-yl)methyl)amino]ethyl)-5-propanecarboxamidefuro[3,2-b]pyridine;

36)2-methyl-3-(2-[N′-methyl-N′-((5-nitropyrimidin-2-yl)methyl)amino]ethyl)-5-(2-propanecarboxamide)furo[3,2-b]pyridine;

37)2-methyl-3-(2-[N′-methyl-N′-((5-dimethylaminopyridazin-3-yl)methyl)amino]ethyl)-5-butanecarboxamidefuro[3,2-b]pyridinebenzoate;

38)2-methyl-3-(2-[N′-methyl-N′-((indazol-5-yl)methyl)amino]ethyl)-5-pentanecarboxamidefuro[3,2-b]pyridine;

39)2-methyl-3-(2-[N′-methyl-N′-((2-aminobenzothiazol-5-yl)methyl)amino]ethyl)-5-(4-fluorobenzamide)furo[3,2-b]pyridinetrifluoromethanesulfonate;

40)2-methyl-3-(2-[N′-methyl-N′-(2-[pyridin-4-yl]ethyl)amino]ethyl)-5-(N-ethylurea)furo[3,2-b]pyridine;

41)2-methyl-3-(2-[N′-methyl-N′-s-butylamino]ethyl)-5-(N-isopropylurea)furo[3,2-b]pyridine;

42)2-methyl-3-(2-[N′-methyl-N′-(2-[pyridin-4-yl]ethyl)amino]ethyl)-5-[N-[(3-methoxy)phenyl]urea]furo[3,2-b]pyridinemalonate.

While all enantiomers, diastereomers, and mixtures thereof, are usefulas 5-HT_(1F) agonists, single enantiomers and single diastereomers arepreferred. Furthermore, while all of the compounds of this invention areusefulias 5-HT_(1F) agonists, certain classes are preferred. Thefollowing paragraphs describe such preferred classes.

1) R is moiety (a);

2) R is moiety (b);

3) R is moiety (c);

4) E—D is CH—CH₂;

5) E—D is C═CH;

6) R¹ is hydrogen;

7) R¹ is C₁-C₄ alkyl;

8) R¹ is methyl;

9) R² is hydrogen;

10) R² is halo;

11) R² is hydroxy;

12) R² is —NR³R⁴;

13) R² is —SR³;

14) R² is —C(O)R³;

15) R² is —C(O)NR³R⁴;

16) R² is —NR³SO₂R⁵;

17) R² is —NHC(Q)NR³R⁴;

18) R² is —NHC(Q)NR³R⁴, and Q is S;

19) R² is —NHC(Q)NR³R⁴, and Q is O;

20) R² is —NHC(O)OR³;

21) R² is —NR³C(O)R⁵;

22) R² is —NR³R⁴ and R³ and R⁴ are taken together with the nitrogen towhich they are attached are selected from the group consisting ofpyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine;

23) R³ is hydrogen;

24) R³ is C₁-C₄ alkyl;

25) R³ is methyl;

26) R³ is C₂-C₆ alkenyl;

27) R³ is C₂-C₆ alkynyl;

28) R³ is —(CH₂)_(n)aryl;

29) R⁴ is hydrogen;

30) R⁴ is C₁-C₄ alkyl;

31) R⁴ is C₂-C₆ alkenyl;

32) R⁴ is C₂-C₆ alkynyl;

33) R⁴ is —(CH₂)_(n)aryl;

34) R⁵ is hydrogen;

35) when R is CH₂CH₂NR³R⁴, R³ is hydrogen and R⁴ is methyl;

36) when R is CH₂CH₂NR³R⁴, R³ is methyl and R⁴ is methyl; R² is selectedfrom the group consisting of benzoylamino, propanoylamino,4-fluorobenzoylamino, 2-thienoylamino, and 2,4-difluorobenzoylamino;

37) R³ is methyl;

38) R³ is ethyl;

39) R³ is propyl;

40) R³ is isopropyl;

41) R³ is phenyl;

42) R³ is allyl;

43) R³ is phenyl monosubstituted with halo;

44) R³ is 4-fluorophenyl;

45) R³ is 4-chlorophenyl;

46) R³ is phenyl (C₁-C₄ alkylene)

47) R³ is benzyl;

48) R³ is phenethyl;

49) R³ and R⁴ taken together with the nitrogen to which they areattached form a morpholine ring;

50) R³ and R⁴ taken together with the nitrogen to which they areattached form a thiomorpholine ring;

51) R³ and R⁴ taken together with the nitrogen to which they areattached form a pyrrolidine ring;

52) R³ and R⁴ taken together with the nitrogen to which they areattached form a piperidine ring;

53) R³ and R⁴ taken together with the nitrogen to which they areattached form a piperazine ring;

54) R³ and R⁴ taken together with the nitrogen to which they areattached form a 4-substituted piperazine ring;

55) R³ is methyl;

56) R³ is ethyl;

57) R³ is propyl;

58) R³ is allyl;

59) R³ is phenyl monosubstituted with C₁-C₄ alkoxy;

60) R³ is 4-methoxyphenyl;

61) R³ is phenyl;

62) any compound exemplified;

63) the compound is an acid addition salt;

64) the compound is the hydrochloride salt;

65) the compound is the oxalate salt; and

66) the compound is the fumarate salt.

It will be understood that the above classes may be combined to formadditional preferred classes.

It is preferred that the mammal to be treated by the administration ofcompounds of this invention is human.

The synthetic methodology required to prepare the compounds of theinvention is well known to those skilled in the art. A suitableelectrophile is reacted with an appropriate 5-aminofuro[3,2-b]pyridineto provide the corresponding ureas, thioureas, sulfonamides, carbamates,and carboxamides of the present invention. This chemistry is illustratedin Scheme 1 where R, R¹, R³, R⁴, and R⁵ are as described supra.

To prepare compounds of the invention where R² is —NR³SO₂R⁵, formulaI(e), a solution of the appropriate 5-aminofuro[3,2-b]pyridine insuitable solvent, such as tetrahydrofuran, dioxane, diethyl ether ordimethylformamide, at a temperature from about 0° C. to about ambient,is reacted with a commercially available R⁵-sulfonyl halide orR⁵-sulfonic anhydride in the presence of a suitable base such aspyridine or triethylamine. The resultant sulfonamide may be isolated bydilution of the reaction mixture with water, adjustment of pH, andextraction with a water immiscible solvent such as dichloromethane. Theproduct may be used for further reactions as recovered, or may bepurified by chromatography, or by recrystallization from a suitablesolvent.

Compounds of the invention where R² is —NHC(Q)NR³R⁴, I(b)/I(c), areprepared by treating a solution of the appropriate5-aminofuro[3,2-b]pyridine (ii) in a suitable solvent, such aschloroform or dichloromethane, with an appropriate isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide. Appropriatecarbamoyl chlorides are available by treating an amine of formula NHR³R⁴with phosgene. When a carbamoyl chloride or carbamoyl bromide is used,the reactions are performed in the presence of a suitable base. Suitablebases include amines typically used as acid scavengers, such as pyridineor triethylamine, or commercially available polymer bound bases such aspolyvinylpyridine. If necessary, an excess of the isocyanate,isothiocyanate, carbamoyl chloride or carbamoyl bromide is employed toensure complete reaction of the starting amine. The reactions areperformed at about ambient to about 80° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction mixture with water and concentrating the remaining organicsunder reduced pressure. When an excess of isocyanate, isothiocyanate,carbamoyl chloride or carbamoyl bromide has been used, however, apolymer bound primary or secondary amine, such as an aminomethylatedpolystyrene, may be conveniently added to react with the excess reagent.Isolation of products from reactions where a polymer bound reagent hasbeen used is greatly simplified, requiring only filtration of thereaction mixture and then concentration of the filtrate under reducedpressure. The product from these reactions may be purifiedchromatographically or recrystallized from a suitable solvent ifdesired. The skilled artisan will appreciate that compounds of theinvention which are ureas may be converted into the correspondingthiourea by treatment with[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](Lawesson'sReagent) or phosphorus pentasulfide.

Compounds of the invention where R² is R³C(O)NH— I(a) or —NR³C(O)OR⁵I(d) are prepared by treating the desired 5-aminofuro[3,2-b]pyridine(ii) with either an appropriate carboxylic acid chloride, bromide oranhydride, or an appropriately substituted chloroformate optionally inthe presence of an acylation catalyst such as dimethylaminopyridine, inthe presence of a suitable base. Suitable bases include amines typicallyused as acid scavengers, such as pyridine or triethylamine, orcommercially available polymer bound bases such as polyvinylpyridine.When an excess of the electrophile is necessary to ensure completereaction of the amine, a polymer bound primary or secondary amine, suchas an aminomethylated polystyrene, may be conveniently added to reactwith the excess reagent. Isolation of products from reactions where apolymer bound reagent has been used is greatly simplified, requiringonly filtration of the reaction mixture to remove the polymer boundconstituents, and then concentration of the filtrate under reducedpressure to isolate the desired product. The product from thesereactions may be purified chromatographically or recrystallized from asuitable solvent if desired.

Alternatively, compounds of the invention where R² is —NR³C(O)R⁵ I(a) or—NHC(O)OR³ I(d) may be prepared by reacting the5-aminofuro[3,2-b]pyridine (ii) with an appropriate carboxylic acid inthe presence of a typical peptide coupling reagent such asN,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexyl-carbodiimide (DCC) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).Polymer supported forms of carbodiimide peptide coupling reagents areuseful for the preparation of compounds of the present invention. Apolymer supported form of EDC, for example, has been described(Tetrahedron Letters, 34 (48), 7685 (1993)). Additionally, a newcarbodiimide coupling reagent,1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC), and itscorresponding polymer supported forms have been discovered and are veryuseful for the preparation of the compounds of the present invention.

Polymers suitable for use in making a polymer supported coupling reagentare either commercially available or may be prepared by methods wellknown to the artisan skilled in the polymer arts. A suitable polymermust possess pendant sidechains bearing moieties reactive with theterminal amine of the carbodiimide. Such reactive moieties includechloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moietyis a chloromethyl group. Additionally, the polymer's backbone must beinert to both the carbodiimide and reaction conditions under which theultimate polymer bound coupling reagents will be used.

Certain hydroxymethylated resins may be converted into chloromethylatedresins useful for the preparation of polymer supported couplingreagents. Examples of these hydroxylated resins include the4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin) and4-benzyloxybenzyl alcohol resin (Wang Resin) available from AdvancedChemtech of Louisville, Ky. (see Advanced Chemtech 1993-1994 catalog,page 115). The hydroxymethyl groups of these resins may be convertedinto the desired chloromethyl groups by any of a number of methods wellknown to the skilled artisan.

Preferred resins are the chloromethylated styrene/divinylbenzene resinsbecause of their ready commercial availability. As the name suggests,these resins are already chloromethylated and require no chemicalmodification prior to use. These resins are commercially known asMerrifield's resins and are available from Aldrich Chemical Company ofMilwaukee, Wis. (see Aldrich 1994-1995 catalog, page 899).

Methods for the preparation of PEPC and its polymer supported forms areoutlined in the following scheme.

Briefly, PEPC is prepared by first reacting ethyl isocyanate with1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with4-toluenesulfonyl chloride to provide PEPC. The polymer supported formis prepared by reaction of PEPC with an appropriate resin under standardconditions to give the desired reagent.

The carboxylic acid coupling reactions employing these reagents areperformed at about ambient to about 45° C., for from about three hoursto about three days. Typically, the product may be isolated by washingthe reaction with water and concentrating the remaining organics underreduced pressure. As discussed supra, isolation of products fromreactions where a polymer bound reagent has been used is greatlysimplified, requiring only filtration of the reaction mixture and thenconcentration of the filtrate under reduced pressure.

The 5-aminofuro[3,2-b]pyridines (ii) required for the preparation of thecompounds of the present invention may be prepared by methods well knownto one of ordinary skill in the art. Compounds of the invention where Ris moiety (a) are derived from the corresponding5-aminofuro[3,2-b]pyridines which may be prepared by the proceduredescribed in Scheme 2 where R¹, R³ and R⁴ are as previously defined.

6-Chloro-2-iodo-3-hydroxypyridine (iii) and an appropriate ester, suchas methyl 4-bromocrotonate (iv) or ethyl 4-bromo-2-pentenoate, arecombined in an appropriate solvent, typically tetrahydrofuran,dimethylformamide or N-methylpyrrolidinone with a suitable base,typically potassium or sodium carbonate, pyridine or triethylamine, andthe reaction mixture heated to reflux until all of the startingsubstituted pyridine has reacted. The resulting compound of formula (v)may then be used directly or purified by crystallization orchromatography. As the skilled artisan would appreciate, the compound offormula (vi) may be prepared through a coupling reaction of a compoundof formula (v), see Larock, et al., Tetrahedron Letters, 1988,29:4687-4690.

Compounds of the invention where R is —CH₂CH(R⁵)NR³R⁴ are prepared fromcompounds of formula (vi). One method of such preparation may firstconsist of converting the ester to an alcohol and then converting thealcohol to an azidoalkane. Such methods may be found in Larock,Comprehensive Organic Transformations, 1989, pp 419. The resultingcompound of formula (vii) may then be used directly or purified bycrystallization or chromatography. The resulting compound of formula(vii) may then be aminated at the halo group, see Buchwald, et al.,Journal of the American Chemical Society, 1997, 119:10539-10540. Theresulting compound of formula (viii) may then be used directly orpurified by crystallization or chromatography. The amine of formula(viii) may then be converted to amide of formula (ix) by procedures wellknown to the skilled artisan, see Larock, Comprehensive OrganicTransformations, 1989, pp 859. The resulting compound of formula (ix)may then be used directly or purified by crystallization orchromatography. The azide of formula (ix) may then be reduced bycatalytic hydrogenation over palladium with an appropriate aldehyde and,if desired, purified by crystallization or chromatography. While theacetamide moiety (x) may be hydrolyzed during the hydrogenation step,the desired 5-aminofuro[3,2-b]pyridine (iia) may be prepared in aseparate hydrolysis step if necessary.

The 6-chloro-3-hydroxy-2-iodopyridine compounds of formula iii may beprepared from commercially available 2-chloro-4-aminopyridine by wellknown methodology. The amine substituent of 2-chloro-4-aminopyridine maybe first converted to the acetate ester via diazonium salt formationfollowed by quenching with acetic anhydride. The ester group may then behydrolyzed under standard conditions; see for example, Greene,“Protective Groups in Organic Synthesis, pg. 162; to liberate thehydroxy group.

The compounds of formula xii may be prepared from compounds of formulaxvi as illustrated in Scheme 4 below where R⁷ is amino, nitro, chloro,bromo, or hydroxy, and R¹, and R³ are as defined above.

For furo[3,2-b]pyridine compounds of formula xii(a) the reaction may beperformed by first reacting a furo[3,2-b]pyridine of formula xvi whereR⁷ is amino or preferably nitro with bromine in acetic acid. Thereaction is typically performed at about 50° C. for about 4 hours. Afterthe bromination is substantially complete, the volatiles are thenremoved under reduced pressure and the residue is subjected to anextractive work-up under basic conditions. The resulting3-bromofuro[3,2-b]pyridine in diethyl ether is then treated with analkyl lithium, typically-n-butyl lithium, in the same solvent, below−100° C. to affect a metal-halogen exchange. After stirring at thistemperature for about 1 hour, the reaction mixture is treated with anequivalent of an appropriate compound of formula xvii. Once the additionof the compound of formula xvii is complete, the reaction mixture isstirred below −78° C. for an additional 3 to 5 hours. It is critical,when R¹ is hydrogen, to maintain the reaction mixture at thistemperature to avoid equilibration of the anion to the 2-position of thebenzofuran ring. The reaction mixture is then allowed to warm to −20° C.over about 50 minutes. An excess of an appropriate base, preferablysodium or potassium hydroxide, in a lower alkanol, typically methanol orethanol is then added and the reaction refluxed for 0.25 to 24 hours toprovide a benzofuran compound of formula xii(a) where R⁷ is amino ornitro.

If desired, compounds of formula xii(a) may be hydrogenated over aprecious metal catalyst to give the corresponding compounds of formulaxii(b). When R⁷ is bromo, a catalyst such as sulfided platinum oncarbon, platinum oxide, or a mixed catalyst system of sulfided platinumon carbon with platinum oxide may be used to prevent hydrogenolysis ofthat bromo substituent during the reduction. The hydrogenation solventmay consist of a lower alkanol, such as methanol or ethanol,tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethylacetate. The hydrogenation may be performed at an initial hydrogenpressure of 20 p.s.i. to 80 p.s.i., preferably from 50 p.s.i. to 60p.s.i., at 0° C. to 60° C., preferably at ambient temperature to 40° C.,for 1 hour to 3 days. Additional charges of hydrogen may be required todrive the reaction to completion depending on the specific substrate.

When the hydrogenation is performed with a compound of formula xii(a)where R⁷ is amino or nitro, more vigorous hydrogenation conditions maybe used without disrupting the rest of the molecule. For example, acatalyst such as platinum or palladium on carbon may be utilized withoutsubstantially effecting deleterious side reactions.

In general, when R⁷ is nitro, that nitro group may be reduced to anamine at any convenient point in the syntheses outlined in Scheme 3 bywell known methodology. See, e.g., Larock, “Comprehensive OrganicTransformations”, pgs. 412-415, VCH Publishers, New York, N.Y., 1989.Additionally, when R⁷ is nitro in compounds of formula xii(a), thatnitro group and the double bond may be hydrogenated simultaneously ifdesired to give a compound of formula xii(b) where R⁷ is amino by manyof the methods described by Larock for the nitro group alone.Furthermore, methods for selective reduction of a double bond in thepresence of a nitro group are known in the art.

When R⁷ is amino, that amino group may be converted to an oxo group viamethods well known to the skilled artisan at any convenient point in thesyntheses outlined in Scheme 3. The amino group may first be treatedwith sodium nitrate and H⁺ and then with POBr₃ to covert the amino groupto bromo. If needed, it is preferred to perform the reaction after theconversion of a compound of formula xii(a) to a compound of formulaxii(b).

When R⁷ is hydroxy, that free hydroxy group may have atrifluoromethanesulfonyl group (SO₂CF₃) installed by standard proceduresknown in the art at any convenient point in the syntheses outlined inScheme 3. For example, a compound of formula xii(a) where R⁷ is hydroxymay be reacted with trifluoromethanesulfonyl chloride ortrifluoromethanesulfonic anhydride in the presence of an appropriatebase to give a compound of formula xii(a) where R⁷ is OSO₂CF₃.

Compounds of formula xvi may be prepared by known procedures such asthat described in Scheme 4 below where R¹ and R⁷ are as defined above.

An a-halo-acetaldehyde of formula xviii, optionally protected as thecorresponding acetal, may be reacted with an appropriately substituted,commercially available, hydroxypyridine of formula xix under standardalkylating conditions to provide the corresponding ether of formula X.This ether may be converted to a benzofuran of formula xvi(a) by heatinga compound of formula xx in the presence of an acid, typicallypolyphosphoric acid or sulfuric acid. When R⁷ is amino in compounds offormula xix or xx, that amino group should be protected with anappropriate amino protecting group as described in Greene. Theprotecting group may be chosen such that it is hydrolyzed during thecyclization step or, if desired, the unprotected compounds of formulaxvi(a) where R⁷ is amino may be prepared in a separate deprotection stepif necessary. Furthermore, these amino compounds of formula xvi(a) maybe converted to the corresponding halo compounds via the Sandmeyerreaction.

Compounds of formula xvii where R is an indolizine may be prepared frommethylvinyl ketone and an appropriate amino-dialkylacetal or -cyclicacetal according to the procedures found in Tet. Let., 24:3281, 1983,and J. C. S. Perk. I, 447, 1986. These acetals are generallycommercially available or can be synthesized by well known methods inthe art from their corresponding commercially available 4-substitutedbutanals. This chemistry is illustrated in Scheme 5, R⁸ and R⁹ are C₁-C₄alkyl or R⁸ and R⁹ taken together with the oxygen atoms, to which theyare attached, form a 5 or 6 membered cyclic acetal.

Compounds of formula xvii(a) may be prepared by acid treatment of theaddition product of methyl vinyl ketone and a compound of formula xxi. Adiethylacetal of formula xxi is a preferred starting material for thisreaction (R⁹ and R⁸ are ethyl). The reaction may be performed by firstdissolving an appropriate aminoacetal of formula xxiii in an suitablesolvent, typically diethyl ether at 0° C., and then adding approximately1.7 equivalents of methyl vinyl ketone. Typically the reaction isallowed to stir at 0° C. for approximately 2 hours before acidificationby addition of, or extraction with, aqueous hydrochloric acid. Usually,the organic layer is removed before heating the aqueous layer toapproximately 100° C. for 1 hour. The resulting compounds of formulaxvii(a) may be isolated from the reaction mixture by adjusting the pH ofthe solution to alkaline and extracting with a water immiscible solventsuch as ethyl acetate or dichloromethane.

Compounds of formula xvii(a) prepared as described in Scheme 5 areracemic and, if used as described in Scheme 3 will produce racemiccompounds of the invention. Compounds of the invention that areoptically enhanced in one enantiomer may be obtained by resolving thecompounds of. formula xvii(a) before use of these compounds as describedin Scheme 5. Methods of resolving enantiomeric compounds of this typeare well known in the art. For example, resolution can be achieved byuse of chiral chromatography. Furthermore, racemic compounds of formulaxvii(a) may be converted to their corresponding diastereomeric mixtureof salts by reaction with a chiral acid such as (+) or (−) tartaricacid. The diastereomers may then be separated and purified byrecrystallization. Once separated, the salts may each be converted backto the chiral free base compounds of formula xvii(a) by reacting thesalts with an aqueous base, such as sodium hydroxide, then extractingthe mixture with a common organic solvent. The optical purity inresolved compounds of formula xvii(a) is maintained while undergoing thechemistry described in this application to afford optically purecompounds of the invention. As an alternative, when advantageous, theresolution techniques just discussed may be performed at any convenientpoint in the syntheses described in Schemes 4-5.

The α-halo aldehydes, or corresponding acetals of formula xviii areeither commercially available or may be prepared from the correspondingacids or acid halides by methods well known to one of ordinary skill inthe art. This chemistry is reviewed by Larock, “Comprehensive OrganicTransformations,” pages 378-379, VCH Publishers, New York, 1989.Compounds of formula xiii, xvi, xvii, xviii, xix, and xxi are known inthe art and, to the extent not commercially available, are readilysynthesized by standard procedures commonly employed in the art such asthose described herein.

The optimal time for performing the reactions of Schemes 1-6 may bedetermined by monitoring the progress of the reaction via conventionalchromatographic techniques, e.g., thin layer chromatography and highperformance liquid chromatography. Furthermore, it is usually preferredto conduct the reactions of Scheme 1-6 under an inert atmosphere, suchas, for example, argon, or, particularly, nitrogen. Choice of solvent isgenerally not critical so long as the solvent employed is inert to theongoing reaction and sufficiently solubilizes the reactants to effectthe desired reaction. The intermediate compounds of this invention arepreferably purified before their use in subsequent reactions. Theintermediates and final products may be purified when, if in the courseof their formation, they crystallize out of the reaction solution. Insuch a situation, the precipitate may be collected by filtration andwashed with an appropriate solvent. Certain impurities may be removedfrom the organic reaction mixture by aqueous acidic or basic extractionfollowed by removal of the solvent by extraction, evaporation, ordecantation. The intermediates and final products of formula I may befurther purified, if desired by common techniques such asrecrystallization or chromatography over solid supports such as silicagel or alumina.

The following Preparations and Examples are provided to better elucidatethe practice of the present invention and should not be interpreted inany way as to limit the scope of same.

To a solution of 2-chloro-5-aminopyridine (30.0 g, 230 mmol) cooled to−10° C. in 120 mL of 3:1 1,2-dimethoxyethane/dichloromethane was added62.1 mL of boron trifluoride diethyl etherate (490 mL) followed by asolution of isobutyl nitrite (32.3 mL, 276 mmol) dissolved in 30 mL of1,2-dimethoxyethane. The reaction was maintained at −10° C. for 0.25 hthen allowed to warm to room temperature over 0.5 h. The mixture wasdiluted with pentane, cooled to 0° C. and filtered. The ivory, solid waswashed with cold pentane, dried in vacuo, and used immediately withoutfurther purification.

The tetrafluoroborate diazonium salt was dissolved in 300 mL of aceticanhydride and heated at 75° C. for 2.5 h. The reaction was cooled,concentrated in vacuo, and partitioned between diethyl ether andsaturated aqueous NaHCO₃. The aqueous layer was extracted with diethylether, and the combined organics were washed with saturated aqueousNaCl, dried (MgSO₄), and concentrated in vacuo. The resulting brownresidue was chromatographed (10% ethyl acetate/hexane) to provide 24.6 g(62%) of the desired material as a white solid.

Calculated for C₇H₆ClNO₂: Theory: C, 49.00; H, 3.52; N, 8.16; Found: C,49.29; H, 3.47; N, 8.12.

2-Chloro-5-acetoxypyridine (21.66 g, 126 mmol) was dissolved in 300 mLof methanol and K₂CO₃ (8.70 g, 63 mmol) was added. The reaction wasstirred at room temperature for approx. 2 h, then concentrated in vacuo.The residue was diluted with diethyl ether and water, and the aqueouslayer was adjusted to neutral pH by the addition of 1N aqueous HCl.Following extraction with diethyl ether, the organics were combined,washed with a solution of saturated aqueous NaCl, dried with MgSO₄, andconcentrated in vacuo. The resulting yellow solid (15.58 g, 96%) wasused without further purification.

A solution of the above material (15.48 g, 119 mmol) and Na₂CO₃ (26.56g, 251 mmol) in water (300 mL) was charged with iodine (30.3 g, 119mmol). The reaction mixture was stirred at room temperature until theiodine color disappeared, approx. 48 h. The solution was adjusted to pH=5 with 1 N aqueous HCl, and extracted with ethyl acetate. The organiclayers were washed with saturated aqueous NaCl, dried over Na₂SO₄, andconcentrated in vacuo.

The resulting white solid was recrystallized from methanol to provide17.8 g (95%) of the title compound.

MS(m/e): 256 (M⁺); Calculated for C₅H₃ClINO: Theory: C, 23.51; H, 1.18;N, 5.48; Found: C, 23.72; H, 1.19; N, 5.45.

A mixture of 6-Chloro-2-iodo-3-hydroxypyridine (10.0 g, 39 mmol), methyl4-bromocrotonate (14 mL, 117 mmol), and K₂CO₃ (16.2 g, 117 mmol) in 250mL of N,N-dimethylformamide was heated at 60° C. for 4 h. The reactionwas cooled, concentrated in vacuo and partitioned between chloroform andwater. Following extraction with chloroform and washing with saturatedaqueous NaCl, the organics were dried over Na₂SO₄ and concentrated invacuo. Column chromatography (0%→30% ethyl acetate/hexane) provided thedesired compound (13.3 g, 97%) as a white solid.

m.p.=112-114° C.; Calculated for C₁₀H₉ClINO₃: Theory: C, 33.97; H, 2.57;N, 3.96; Found: C, 34.27; H, 2.72; N, 3.95.

The title compound was prepared in 99% isolated yield in the same manneras methyl 4-(6-chloro-2-iodopyridyloxy)but-2-enoate, utilizing methyl4-bromo-2-pentenoate (Löffler, A. et al. Helv. Chim. Acta, 1970, 53,403-417) as the electrophile.

MS(m/e): 368 (M⁺); Calculated for C₁₁H₁₁ClINO₃: Theory: C, 35.94; H,3.02; N, 3.81; Found: C, 35.70; H, 2.97; N, 3.81.

To a solution of methyl 4-(6-chloro-2-iodopyridyloxy)but-2-enoate (5.87g, 16.6 mmol) dissolved in 150 mL of N,N-dimethylformamide was added4.39 g of Na₂CO₃ (42 mmol), 1.13 g of sodium formate (16.6 mmol), 5.07 gof tetrabutylammonium chloride (18.0 mmol), and 0.19 g of palladium(II)acetate (0.8 mmol). The reaction mixture was heated at 80° C. for 3 h,then concentrated in vacuo. The residue was partitioned betweenchloroform and water, and the aqueous layer was extracted withchloroform. The combined organics were washed with saturated aqueousNaCl, dried over Na₂SO₄, and concentrated. Upon column chromatography(0%→40% ethyl acetate/hexane), the desired compound was isolated as anivory solid (3.66 g, 98%).

m.p.=92-93° C.; MS(m/e): 226 (M⁺); Calculated for C₁₀H₈ClNO₃: Theory: C,53.23; H, 3.57; N, 6.21; Found: C, 53.20; H, 3.61; N, 5.96.

The title compound was prepared in 70% isolated yield in the mannerdescribed in Preparation 6.

m.p.=166-167° C.; MS(m/e): 240 (M⁺); Calculated for C₁₁H₁₀ClNO₃: Theory:C, 55.13; H, 4.21; N, 5.84; Found: C, 55.18; H, 4.07; N, 6.07.

To a solution of 3-carbomethoxy-5-chlorofuro[3,2-b]pyridine (3.0 g, 13mmol) cooled to −78° C. in tetrahydrofuran (125 mL) was addeddiisobutylaluminum hydride (1 M in hexane, 40 mL, 40 mmol). The reactionmixture was maintained at −78° C. for 0.25 h, warmed to room temperatureover a period of 1 h, then poured into a solution of 2 M aqueous sodiumpotassium tartrate. After stirring vigorously at room temperatureovernight, the aqueous layer was extracted with ethyl acetate. Thecombined organics were washed with saturated aqueous NaCl, dried overNa₂SO₄, and concentrated in vacuo.

The resulting crude alcohol was cooled to 0° C. in dichloromethane (150mL), and charged with triethylamine (4.1 mL, 29 mmol) followed bymethanesulfonyl chloride (1.4 mL, 17 mmol). The reaction was warmed toroom temperature and stirred for 2 h, then poured into a saturatedsolution of NaHCO₃. Following extraction with dichloromethane, theorganic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄,and concentrated to provide an amber oil.

To the crude mesylate dissolved in N,N-dimethylformamide (100 mL) wasadded sodium azide (2.6 g, 40 mmol). The reaction was stirred at roomtemperature overnight, then poured into water. The mixture was extractedwith ethyl acetate, and the combined organics were washed with saturatedaqueous NaCl, dried over Na₂SO₄, and concentrated. Column chromatography(0→20% ethylacetate/hexane) provided the desired azide (2.4 g, 80%).

m.p.=55-57° C.; Calculated for C₉H₇ClN₄O: Theory: C, 48.55; H, 3.17; N,25.17; Found: C, 48.74; H, 3.13; N, 25.43.

The title compound was prepared in 75% isolated yield in the 3-stepprocedure described in Preparation 8.

MS(m/e): 237 (M⁺); Calculated for C₁₀H₉ClN₄O: Theory: C, 50.75; H, 3.83;N, 23.67; Found: C, 50.75; H, 3.79; N, 23.65.

A solution of 3-(2-azidoethyl)-5-chlorofuro-[3,2-b]pyridine (2.32 g,10.40 mmol) dissolved in toluene (300 mL) was treated withtris(dibenzylideneacetone)dipalladium(0) (0.48 g, 0.52 mmol),(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.65 g, 1.04mmol), sodium tert-butoxide (1.40 g, 14.00 mmol), and4-methoxybenzylamine (1.73 g, 12.00 mmol). The reaction was heated at80° C. overnight. Upon cooling to room temperature, the reaction waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate, and the combined organics were washed withsaturated aqueous NaCl, dried over Na₂SO₄, and concentrated. Columnchromatography (0→25% ethyl acetate/hexane) provided the title compoundas a yellow oil (3.14 g, 93%).

Calculated for C₁₇H₁₇N₅O₂: Theory: C, 63.15; H, 5.30; N, 21.66; Found:C, 63.55; H, 5.60; N, 21.33.

The title compound was prepared in 79% isolated yield from2-methyl-3-(2-azidoethyl)-5-chlorofuro[3,2-b]pyridine in the mannerdescribed in Preparation 10.

MS(m/e): 338 (M⁺); Calculated for C₁₈H₁₉N₅O₂: Theory: C, 64.08; H, 5.68;N, 20.76; Found: C, 64.10; H, 5.94; N, 20.75.

To a rapidly stirring mixture of3-(2-azidoethyl)-5-(4-methoxyphenylmethylamino)furo[3,2-b]pyridine (2.89g, 8.9 mmol) dissolved in 300 mL of dichloromethane was added water (10mL) followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (4.68 g,20.5 mmol). After 2 h at room temperature, a solution of 1 M aqueousNa₂S₂O₃ (100 mL) was added, and the reaction was stirred an additional0.25 h. Following extraction with chloroform, the combined organics werewashed with saturated aqueous NaCl, dried over Na₂SO₄, and concentrated.The crude amine was purified via solid phase extraction (Varian MegaBond Elut® SCX column, eluting with 2 M ammonia-methanol), andconcentrated in vacuo. The amine was dissolved in pyridine (250 mL) andtreated with acetyl chloride (1.05 mL, 13.4 mmol). The reaction washeated at 55° C. for 3 h, then concentrated in vacuo. After partitioningbetween dichloromethane and 0.1 M aqueous NaOH, the aqueous layer wasextracted with dichloromethane, and the combined organic layers werewashed with saturated aqueous NaCl, dried over Mg₂SO₄, and concentratedin vacuo. Column chromatography on silica gel (0→80% ethylacetate/hexane) provided the title compound (1.78 g, 81% yield) as ayellow solid.

m.p.=100-101° C.; MS(m/e): 246 (M⁺); Calculated for C₁₁H₁₁N₅O₂: Theory:C, 53.87; H, 4.52; N, 28.56; Found: C, 53.96; H, 4.67; N, 28.33.

The title compound was prepared in 68% isolated yield from2-methyl-3-(2-azidoethyl)-5-(4-methoxyphenylmethylamino)furo[3,2-b]pyridineusing the method described in Preparation 12.

MS(m/e): 260 (M⁺); Calculated for C₁₂H₁₃N₅O₂: Theory: C, 55.59; H, 5.05;N, 27.01; Found: C, 55.87; H, 5.17; N, 26.92.

To a solution of 5-acetylamino-3-(2-azidoethyl)furo[3,2-b]pyridine (1.65g, 6.5 mmol) dissolved in ethanol (300 mL) was added 200 mg of 10%palladium on carbon. The mixture was hydrogenated at room temperatureunder 30 psi of hydrogen pressure for 2 h, filtered through celite, andconcentrated in vacuo. The crude material was dissolved in methanol (180mL), cooled to 0° C., and treated with sodium cyanoborohydride (0.41 g,16.2 mmol), acetic acid (2.0 mL, 32.4 mmol), and formaldehyde (37 wt. %in water, 1.66 mL, 19.5 mmol). The reaction was warmed to roomtemperature and stirred overnight. The solvent was removed, and thesolid residue was partitioned between 3:1 chloroform/isopropyl alcoholand water. The aqueous layer was adjusted to pH=14 with 1 N aqueousNaOH, extracted with chloroform, and the combined organics were washedwith saturated aqueous NaCl, dried over Na₂SO₄, and concentrated. Theresidue was chromatographed on silica gel (0→20% 2 MNH₃-methanol/dichloromethane) to provide 1.26 g (79%) of the desiredmaterial. An analytical sample of the oxalate salt was prepared.

m.p.=168-170° C.; MS(m/e): 248 (M⁺); Calculated for C₁₃H₁₇N₃O₂·C₂H₂O₄:Theory: C, 53.41; H, 5.68; N, 12.46; Found: C, 53.57; H, 5.91; N, 12.57.

The title compound was prepared from5-acetylamino-3-(2-azidoethyl)-2-methylfuro[3,2-b]pyridine in the mannerdescribed in Preparation 14 in 83% isolated yield.

m.p.=138-139° C.; MS(m/e): 260 (M⁺); Calculated for C₁₄H₁₉N₃O₂: Theory:C, 64.35; H, 7.33; N, 16.08; Found: C, 64.14; H, 7.09; N, 16.07.

A solution of5-acetylamino-3-[2-(N,N-dimethylamino)ethyl]furo[3,2-b]pyridine (1.26 g,5.10 mmol) dissolved in 120 mL of 1 N aqueous HCl was heated at 70° C.for 3 h. The reaction was cooled to room temperature, basified to pH >12with 5 N aqueous NaOH, and extracted with 3:1 chloroform/isopropylalcohol. The combined organic extracts were washed with saturatedaqueous NaCl, dried over Na₂SO₄, and concentrated. Chromatography (0→20%2 M NH₃-methanol/dichloromethane) provided the desired material (85%yield) as white solid. A sample of the oxalate salt was prepared foranalysis.

m.p.=122-124° C.; MS(m/e): 206 (M⁺); Calculated for C₁₁H₁₅N₃O·C₂H₂O₄·0.5CH₄O: Theory: C, 52.08; H, 6.15; N, 13.50; Found: C, 52.03; H, 6.03; N,13.51.

The title compound was prepared from5-acetylamino-3-[2-(N,N-dimethylamino)ethyl]-2-methylfuro[3,2-b]pyridinein the same manner as5-amino-3-[2-(N,N-dimethylamino)ethyl]furo[3,2-b]pyridine, providing thetitle compound as an amorphous white solid (79%).

m.p.=103-104° C.; MS(m/e): 220 (M⁺); Calculated for C₁₂H₁₇N₃O: Theory:C, 65.73; H, 7.81; N, 19.16; Found: C, 65.65; H, 7.84; N, 18.93.

EXAMPLE 1 & 2 5-Amido-3-2-(N,N-dimethylamino)ethyl]furo[3,2-b]pyridineand 5-Amido-3-[2-(N,N-dimethylamino)ethyl]-2-methylfuro[3,2-b]pyridine

To a solution of the appropriate 5-aminofuro[3,2-b]pyridine preparedabove (0.37 mmol) dissolved in 15 mL of pyridine was added the acidchloride (0. 52 mmol). The reaction mixture was heated at 55° C. for 2h, then concentrated in vacuo. The residue was partitioned between 3:1chloroformn/isopropyl alcohol and 0.1 N aqueous NaOH. The aqueous layerwas extracted with chloroform and the combined organics were washed withsaturated aqueous NaCl, dried over Na₂SO₄, and concentrated.Chromatography (0→10% 2 M NH₃-methanol/dichloromethane) provided thetitle compound which was analyzed either as the free base or convertedto the oxalate salt.

Examples 3-12 were prepared and isolated in the same manner as Examples1-2.

EXAMPLE 33-[2-(N,N-Dimethylamino)ethyl]-5-propanoylaminofuro[3,2-b]pyridineOxalate

The title compound was isolated in 83% yield as the oxalate salt.

m.p.=153-155° C.; Calculated for C₁₄H₁₉N₃O₂·C₂H₂O₄·0.5 CH₄O: Theory: C,54.31; H, 6.17; N, 11.69; Found: C, 54.38; H, 6.19; N, 11.35.

EXAMPLE 45-Benzoylamino-3-[2-(N,N-dimethylamino)ethyl]furo[3,2-b]pyridine Oxalate

The title compound was isolated in 73% yield as the oxalate salt.

m.p.=65-66° C.; Calculated for C₁₈H₁₉N₃O₂·C₂H₂O₄: Theory: C, 60.14; H,5.30; N, 10.52; Found: C, 60.39; H, 5.45; N, 10.46.

EXAMPLE 53-[2-(N,N-Dimethylamino)ethyl]-5-(4-fluorobenzoyl)aminofuro[3,2-b]pyridineOxalate

The title compound was isolated in 80% yield as the oxalate salt.

m.p.=124-126° C.; MS(m/e): 328 (M⁺); Calculated for C₁₈H₁₈FN₃O₂·C₂H₂O₄:Theory: C, 57.55; H, 4.83; N, 10.07; Found: C, 57.85; H, 4.95; N, 10.15.

EXAMPLE 6 3-[2-(N,N-Dimethylamino)ethyl]-5-(2-thienoyl)aminofuro[3,2-b]pyridine Oxalate

The title compound was isolated in 83% yield as the oxalate salt.

m.p.=68-69° C.; MS(m/e): 330 (M⁺); Calculated for C₁₆H₁₇N₃O₂S·C₂H₂O₄:Theory: C, 53.33; H, 4.72; N, 10.36; Found: C, 53.51; H, 4.64; N, 10.34.

EXAMPLE 75-(2,4-Difluorobenzoyl)amino-3-[2-(N,N-dimethylamino)ethyl]furo[3,2-b]pyridineOxalate

The title compound was isolated in 90% yield as the oxalate salt.

MS(m/e): 346 (M⁺).

EXAMPLE 83-[2-(N,N-Dimethylamino)ethyl]-2-methyl-5-propanoylaminofuro[3,2-b]pyridineOxalate

The title compound was isolated in 80% yield as the oxalate salt.

m.p.=168-170° C.; MS(m/e): 276 (M⁺); Calculated forC₁₄H₁₉N₃O₂·C₂H₂O₄·0.5 CH₄O: Theory: C, 55.11; H, 6.61; N, 11.02; Found:C, 55.31; H, 6.54; N, 10.81.

EXAMPLE 95-Benzoylamino-3-[2-(N,N-dimethylamino)ethyl]-2-methylfuro[3,2-b]pyridine

The title compound was isolated in 74% yield as the free base.

m.p.=119-120° C.; MS(m/e): 324 (M⁺); Calculated for C₁₉H₂₁N₃O₂: Theory:C, 70.57; H, 6.55; N, 12.99; Found: C, 70.32; H, 6.81; N, 12.92.

EXAMPLE 103-[2-(N,N-Dimethylamino)ethyl]-5-(4-fluorobenzoyl)amino-2-methylfuro[3,2-b]pyridineOxalate

The title compound was isolated in 80% yield as the oxalate salt.

m.p.=136-138° C.; MS(m/e): 342 (M⁺); Calculated forC₁₄H₁₉N₃O₂·C₂H₂O₄·0.25 CH₄O: Theory: C, 58.08; H, 5.28; N, 9.56; Found:C, 57.33; H, 5.05; N, 9.28.

EXAMPLE 11 3-[2-(N,N-Dimethylamino)ethyl]-2-methyl-5-(2thienoyl)aminofuro[3,2-b]pyridine Oxalate

The title compound was isolated in 90% yield as the oxalate salt.

m.p.=211-212° C.; MS(m/e): 330 (M⁺); Calculated for C₁₇H₁₉N₃O₂S·C₂H₂O₄:Theory: C, 54.41; H, 5.05; N, 10.02; Found: C, 54.65; H, 4.97; N, 10.06.

EXAMPLE 125-(2,4-Difluorobenzoyl)amino-3-[2-(N,N-dimethylamino)ethyl]-2-methylfuro[3,2-b]pyridine

The title compound was isolated in 74% yield as the free base.

MS(m/e): 360 (M⁺).

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds employed, the type of pharmacokinetic profiledesired from the route of administration and the compound(s), and thestate of the patient.

Formulations amenable to oral or injectable administration are preparedin a manner well known in the pharmaceutical art and comprise at leastone active compound. See, e.g., Remington's Pharmaceutical Sciences,(16th ed. 1980).

In general, a formulation of the present invention includes an activeingredient (a compound of formula I) and is usually mixed with anexcipient, diluted by an excipient or enclosed within such a carrierwhich can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be a solid, semi-solid,or liquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the formulations can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing for example up to 10% by weight of theactive compound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g., about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompounds of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The following formulation examples are illustrative only and are notintended to limit the scope of the present invention. The term “activeingredient” refers to a compound of formula I.

FORMULATION EXAMPLE 1 Hard Gelatin Capsules

Quantity Ingredient (mg/capsule) 2-methyl-3-(2-[N′-methyl-N′-s- 30.0butylamino]ethyl)-5-isobutyramide- furo[3,2-b]pyridine Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2 Tablet

Quantity Ingredient (mg/tablet) 2-methyl-3-(2-[N′-methyl-N′- 25.0(2-[pyridin-4-yl]-ethyl)amino]- ethyl)-5-(4-fluorobenzamide)furo-[3,2-b]pyridine malonate Cellulose, microcrystalline 200.0 Colloidalsilicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3 Dry Powder Inhaler

Ingredient Weight % 2-methyl-3-(2-[N′-methyl-N′- 5([2-aminobenzothiazol-5-yl]- methyl)amino]ethyl)-5- (4-fluorobenzamide)-furo[3,2-b]pyridine Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

FORMULATION EXAMPLE 4 Tablet

Quantity (mg/ Ingredient tablet) 2-methyl-3-(2-[N′-methyl-N′- 30.0([thiazol-2-yl]methyl)amino]ethyl)- 5-cycloheptanecarboxamidefuro-[3,2-b]pyridine Starch 45.0 Microcrystalline cellulose 35.0Polyvinylpyrrolidone 4.0 (as 10% solution in water) Sodium carboxymethylstarch 4.5 Magnesium stearate 0.5 Talc 1.0 Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C.-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5 Capsules

Quantity (mg/ Ingredient capsule) 2-methyl-3-(2-[N′-methyl-N′- 40.0(2-[1-isopropylpyrazol-4-yl]- ethyl)amino]ethyl)-5-butyramidefuro[3,2-b]pyridine Starch 109.0 Magnesium stearate 1.0 Total150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6 Suppositories

Ingredient Amount 3-(2-[N′-methyl-N′-([4- 25 mg bromothien-2-yl]methyl)-amino]ethyl)-5-(4-fluoro- benzamide)furo[3,2-b]pyridine Saturated fattyacid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7 Suspensions

Ingredient Amount 2-ethyl-3-(2-[N′-ethyl-N′-(2- 50.0 mg(3-methylthiobenzofur-5-yl]ethyl)- amino]ethyl)-5-(pyridine-2-carboxamide)furo[3,2-b]pyridine; Xanthan gum 4.0 mg Sodium carboxymethylcellulose (11%) 50.0 mg Microcrystalline cellulose (89%) Sucrose 1.75 gSodium benzoate 10.0 mg Flavor and color q.v. Purified water to 5.0 ml

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION EXAMPLE 8 Capsules

Quantity (mg/ Ingredient capsule) 2-propyl-3-(2-[N′-isopropyl-N′- 15.0(3-[isobenzofur-2-yl]propyl)amino]- ethyl)-5-(4-fluorobenzamide)-furo[3,2-b]pyridine Starch 407.0 Magnesium stearate 3.0 Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

FORMULATION EXAMPLE 9 Intravenous Formulation

Ingredient Quantity 2-methyl-3-(2-[N′-butyl-N′- 250.0 mg([pyrrol-3-yl]methyl)amino]ethyl)- 5-(4-fluorobenzamide)furo-[3,2-b]pyridine Isotonic saline 1000 ml

FORMULATION EXAMPLE 10 Topical Formulation

Ingredient Quantity 2-methyl-3-(2-[N′-methyl-N′- 1-10 g([5-cyanoimidazol-2-yl]methyl)amino]-ethyl)-5-acetamidefuro[3,2-b]pyridine Emulsifying wax 30 g Liquidparaffin 20 g White soft paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11 Sublingual or Buccal Tablets

Quantity (mg/ Ingredient tablet) 2-methyl-3-(2-[N′-methyl-N′- 10.0([isoquinolin-7-yl]methyl)amino]ethyl)-5- cyclobutanecarboxamidefuro-[3,2-b]pyridine Glycerol 210.5 Water 143.0 Sodium citrate 4.5 Polyvinylalcohol 26.5 Polyvinylpyrrolidone 15.5 Total 410.0 mg

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and the activeingredient is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These formulations can be administered by a varietyof routes including oral, buccal, rectal, intranasal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Many of thecompounds employed in the methods of this invention are effective asboth injectable and oral compositions.

In order to administer transdermally, a transdermal delivery device(“patch”) is needed. Such transdermal patches may be used to providecontinuous or discontinuous infusion of a compound of the presentinvention in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. No. 5,023,252, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, which is herein incorporated byreference. The delivery of hydrophilic drugs may be enhanced byintra-arterial infusion of hypertonic solutions which can transientlyopen the blood-brain barrier.

A compound of formula I is preferably formulated in a unit dosage form,each dosage containing from about 0.001 to about 100 mg, more usuallyabout 1.0 to about 30 mg, of the active ingredient. The term “unitdosage form” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient as described above.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.0001 to about 30 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.1 to about 15 mg/kg/day, in single ordivided dose, is especially preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound or compounds administered, the age, weight, and responseof the individual patient, and the severity of the patient's symptoms,and therefore the above dosage ranges are not intended to limit thescope of the invention in any way. In some instances dosage levels belowthe lower limit of the aforesaid range may be more than adequate, whilein other cases still larger doses may be employed without causing anyharmful side effect, provided that such larger doses are first dividedinto several smaller doses for administration throughout the day.

We claim:
 1. A compound of formula I:

and pharmaceutical acid addition salts thereof, where; R is

E—D is C═CH or CH—CH₂; R¹ is hydrogen or C₁-C₄ alkyl; R² is hydrogen,halo, hydroxy, —NR³R⁴, —SR³, —C(O)R³, —C(O)NR³R⁴, —NR³SO₂R⁵,—NHC(Q)NR³R⁴, —NHC(O)OR³, or —NR³C(O)R⁵; R³, R⁴, and R⁵ areindependently hydrogen, C₁-C₄ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or—(CH₂)_(n)aryl; or R³ and R⁴ combine, together with the nitrogen towhich they are attached, form a pyrrolidine, piperidine, piperazine,4-substituted piperazine, morpholine, or thiomorpholine ring; n is 0, 1,2, 3, 4, 5, or 6; and Q is O or S.
 2. The compound of claim 1 where R ismoiety (a).
 3. The compound of claim 2 where R³ is C₁-C₄ alkyl.
 4. Thecompound of claim 2 where R⁶ is C₁-C₄ alkyl.
 5. The compound of claim 2where R¹ is methyl.
 6. The compound of claim 4 where R³ is methyl and R⁴is methyl.
 7. The compound of claim 1 where R is moiety (c).
 8. Thecompound of claim 7 where R³ is C₁-C₄ alkyl.
 9. The compound of claim 8where R³ is methyl.
 10. The compound of claim 8 where R² is —NHC(O)R⁵.11. The compound of claim 9 where R² is —NHC(O)R⁵.
 12. A pharmaceuticalformulation comprising a compound of claim 1 and a pharmaceuticalcarrier, diluent, or excipient.
 13. A pharmaceutical formulationcomprising a compound of claim 7 and a pharmaceutical carrier, diluent,or excipient.
 14. A pharmaceutical formulation comprising a compound ofclaim 11 and a pharmaceutical carrier, diluent, or excipient.
 15. Amethod for treating migraine in a mammal comprising administering to amammal in need of such treatment an effective amount of a compound ofclaim 1, or a pharmaceutical acid addition salt thereof.
 16. A methodfor treating migraine in a mammal comprising administering to a mammalin need of such treatment an effective amount of a compound of claim 2,or a pharmaceutical acid addition salt thereof.
 17. A method fortreating migraine in a mammal comprising administering to a mammal inneed of such treatment an effective amount of a compound of claim 7, ora pharmaceutical acid addition salt thereof.
 18. A method for treatingmigraine in a mammal comprising administering to a mammal in need ofsuch treatment an effective amount of a compound of claim 11 or apharmaceutical acid addition salt thereof.